Purpose: Organ motion may have an impact on the radiation dose administered in
radiotherapy. Motion can occur during treatment (intrafractional motion) or between fractions
of treatment (interfractional motion). A clinically relevant dosimetric impact on OAR would mean that additional measures such as 4D-CT planning or a PRV are needed. In this study, the
dosimetric impact of intra- and interfractional motion is studied for TBI delivered with VMAT is studied.
Method: For the intrafractional part, motion magnitude was determined with 4D-CT data, and this magnitude was used to expand and reduce the volumes of the OAR in 27 VMAT-TBI plans, dose was analyzed in these volumes. For the interfractional part, the CBCT images taken right before treatment are registered with the planning CT. The planning CT is then deformed to match the anatomy of the CBCT for each fraction. The dose is recalculated on this deformed CT and the mean dose in OAR volumes is evaluated for each fraction.
Results: For the intrafractional part, on average, an expansion with a typical respiratory motion magnitude results in a 0.3 Gy higher mean dose in the kidneys. This expansion results in a 0.6 Gy higher mean dose in the left lung and a 0.8 Gy higher dose in the right lung. For the interfractional part, the mean dose difference between the fraction with the lowest mean dose and the one with the highest mean dose was 0.04 Gy on average.
Conclusion: After discussing these dose differences with a radiooncologist, it was concluded that these differences were not clinically relevant. Therefore, 4D-CT planning and a PRV are
not necessary.

Background Dynamic SPECT scanning provides a non-invasive way to image the time-dependent distribution of radio-labelled tracers inside living tissue. Beside human medicine, dynamic SPECT also finds its applications in pre-clinical research on small animals. In pre-clinical research, multi-pinhole collimators are used to enable high-resolution sub-millimeter imaging. Conventional iterative reconstruction methods, such as Maximum Likelihood Expectation Maximisation (MLEM) perform poorly in reconstructing the noisy and low-count scans in dynamic SPECT. This limits the temporal resolution that can be achieved.
Method The reconstruction of noisy, low-count time-frames can be aided by incorporating information from earlier and later time-frames. Wang and Qi (2015) published the paper 'PET Image Reconstruction Using Kernel Method', with a proposed method entitled Kernelised Expectation Maximisation (KEM) for dynamic PET, a method that uses principles from Machine Learning, such as Support Vector Machines and the 'kernel trick' to incorporate prior information in the reconstruction algorithm. This method is highly adjustable due to a number of input parameters of the method. In this paper, KEM is implemented for dynamic multi-pinhole SPECT. The effects of the KEM parameters are explored in computer simulations. Two different dynamic phantoms are used, one of the striata in a mouse brain which were adapted from a paper by Vastenhouw et al. (2007) and one of the hepatobiliary system adapted from Vaissier et al. (2012). The results of KEM are benchmarked against conventional MLEM with a Gaussian post-filter. 
Results In high-count simulations, the MLEM reconstructions had a lower mean-squared-error than the KEM image, while the signal-to-noise ratio of KEM was better than MLEM. The images produced after 200 iterations were indistinguishable, however. In the low-count regime, KEM was shown to be more resistant to noise than MLEM. Varying the input parameters of KEM gave rise to differences in performance, such as (over-)smoothing effects and a different level of noise-suppresion in the reconstructed image. 
Conclusions In the simulations used in this paper, KEM was shown to outperform conventional MLEM with a Gaussian post-filter from low-count projections. The optimal input parameters of the KEM algorithm, however, need to be found ad hoc by searching the parameter space. Further research should look into finding a set of rules or guidelines for finding the optimal parameters.

The goal of radiotherapy is to maximize the dose to the target while minimizing the dose to normal tissue. Treatment plans are optimized for this goal and dose delivery is improved in accuracy and precision. The optimization is based on the delineations of the volumes of interest on the medical images of the patient. The problem is that these delineations contain uncertainties and the effect of these uncertainties become more pronounced as the accuracy and precision of dose delivery improves. The delineation uncertainties are caused by various factors such as knowledge and experience of the observers, guidelines, and image quality and modality. The goal of this thesis is to research the effects of delineation uncertainties. Uncertainties are characterized using a rolling ball algorithm (RBA) to modify the delineation. The radius of the ball represents the uncertainty and ranges from -5 mm to 5 mm for the clinical target volume (CTV) and -2 mm to 2 mm for the brain stem. The effect of these uncertainties will be researched for both fixed and re-optimized dose distributions. These are then used as input to create a model that will simulate the dose distributions for different uncertainties using Polynomial Chaos Expansion (PCE). PCE will be used to model dose volume histograms (DVH) of the CTV and the brain stem. The dosimetric effect will be determined by setting confidence intervals in D98% of the CTV and D2% of the brain stem. The widths of the confidence intervals in these two metrics represent the dose uncertainty. This thesis uses three sets of patient data. Each patient had a CTV close to the brain stem. Dose uncertainty in the two metrics was found to increase as the uncertainty of CTV and brain stem delineation increases. For a fixed dose distribution, a delineation uncertainty of 0.75 mm to 1.25 mm in the CTV would lead to a dose uncertainty of 2 Gy in the D98% of the CTV. A delineation uncertainty of 0.25 mm to 0.5 mm in the brain stem would lead to the same dose uncertainty in D2% of the brain stem. For a re-optimized dose distribution, a combined delineation uncertainty of 1.25 mm for two patients and 4.5 mm for one patient would lead to a dose uncertainty of 2 Gy in D98% of the CTV. For the same dose uncertainty in the D2% of the brain stem, there would be a combined delineation uncertainty between 1.0 mm and 4.5 mm. For all three patients, the dose uncertainty in the D2% was more sensitive to delineation uncertainties in the brain stem. The effects of these uncertainties will depend on the nominal situation. For all patients a 2 Gy dose uncertainty corresponds to 2.85% of the prescribed dose to the CTV and 3.33% of the maximum dose constraint of the brain stem. One patient was on the boundary of underdosing the CTV in the nominal situation and a 2 Gy uncertainty would be sufficient to underdose the CTV. The nominal D2% for all three patients was sufficiently low that it is unlikely it would exceed the maximum dose constraint.

A radioisotope used in radionuclide therapy is Holmium-166 (Ho-166). The treatment effectiveness of Ho-166 could be improved by the use of a so called in vivo Dysprosium-166(Dy-166)/Ho-166 generator. The application of this generator is hindered by an effect called internal conversion (IC). This affect can arise after the decay of Dy-166 to Ho-166, which can cause separation of Ho-166 from its carrier.
Polymeric micelles might form a solution in the application of the Dy-166/Ho-166 generator in radionuclide therapy. The main goal of this thesis was to investigate and understand the loading mechanism of metallic species and polymeric micelles with a focus on the loading of Dy/Dy-166 and Ho-166.

It was found that it was not effective to load metallic species (Dy/Dy-166) as free ions or as solid precipitates. Loading metallic species as aqueous hydroxides showed to be crucial for achieving a good loading and high stability. The second goal was to study if polymeric micelles were able to retain Ho-166 inside their core under the effects of internal conversion. No additional losses of Ho-166 were found when Dy/Dy-166 and Ho-166 were loaded into the micelles. It was concluded that the PCL-PEO micelles prevented the loss of Ho-166 under internal conversion effects.

Cancer is a disease that causes almost 10 million deaths each year. Currently, there is no perfect treatment for it. However, there is a promising treatment called proton radiotherapy. This works almost the same as one of the older cancer treatments called photon radiotherapy. However, radiotherapy with protons has an advantage in comparison with radiotherapy with photons. This advantage lies in the way the protons lose their energy when going through tissue. The protons deliver most of their dose in a very small region. Cause of this advantage, proton radiotherapy can deliver a lot of dose into the tumour while minimizing the dose delivered into healthy tissue. But this advantage can change into a disadvantage when the location of the tumour moves a few millimeters.
Therefore ideally a scan is taken each time the patient comes in, so the location of the tumour is known very accurately. After the scan it is best to immediately create a treatment plan and do the treatment session. But creating a treatment plan takes to much time to be able to do that. Mainly, this is because the calculation of the dose distribution is not fast enough. This report studies a faster method for the calculation of the dose distribution. The method is derived by the Medical Physics \& Technology group from TU Delft. This method is currently not accurate enough to use for treatment planning. The problem of the method is that the dose due to nuclear interactions is not included correctly. The goal of this report is to make the method more accurate by adding the nuclear dose caused by secondary particles formed due to inelastic nuclear interactions to the dose calculated by the existing method.
The nuclear dose is calculated using a convolution of a kernel with the proton flux. The nuclear dose of the following secondary particles is calculated: alpha particles, deuteron particles and secondary protons. Adding the nuclear dose caused by these three secondary particles increased the accuracy of the model by 0.36 percent. However adding the nuclear dose calculation increased the time needed to calculate the dose distribution with 18625 percent. By calculating the convolution using the fast Fourier transform this could be decreased by a factor of 11. However adding the nuclear dose calculation to the fast method increases the time needed to calculate the dose distribution too much. Therefore the calculation of the dose distribution is not fast enough to scan a patient and immediately start with the best possible treatment plan using the fast method with the nuclear dose calculation added.

Most modern cancer treatments are a combination of therapies. In approximately 50% of these combinations radiation therapy plays a prominent role. Although external radiation therapy is very effective,
it still damages healthy tissue. Therefore, ways to increase radiation dose deposition at the tumor are sought. The interaction of radiation with the photocatalytic nanoparticle titanium dioxide, TiOኼ NPs, is investigated in effort to improve the effectiveness of radiation therapy, minimizing collateral damage to healthy tissue.
TiOኼ NPs, upon the absorption of light, are capable of producing reactive oxygen species, which are the main contributor to DNA strand breakage and cell damage through oxidative reactions in radiation therapy. Singlet oxygen is the most potent of these reactive oxygen species. This research aims to
determine whether TiOኼ NPs are capable of producing singlet oxygen when interacting with ionizing radiation. Efforts are made in uncovering the mechanisms and dependencies behind the production of singlet oxygen using the fluorescent probe Singlet Oxygen Sensor Green, SOSG. The oxidative capabilities of the TiOኼ NPs in combination with ionizing radiation are looked into with the probe Mythelene blue, MB, which degrades under oxidative reactions.
The results for aerobic conditions show a significant rise in fluorescent intensity by the probe SOSG when irradiated in the presence TiOኼ NPs. The rise in fluorescence appears to be linked to the presence of singlet oxygen but this could not be confirmed. SOSG has also shown a rise in fluorescence in
anaerobic circumstances not suitable for singlet oxygen production. This signal response is attributed to the increased presence of hydrated electrons, in line with hypothesized sensitivity of SOSG towards hydrated electrons. The mechanisms behind the production of singlet oxygen could not be uncovered
however the production does favour low photon energies and does not depend on dose rate.
The results from the MB degradation experiments indicate no significant amount of degradation is caused by the photocatalytic activity of TiOኼ NPs concentrations used in this thesis. The degradation that does occur is due to radiolysis, which favours low photon energies due to the increased absorbance.
The production of singlet oxygen through the oxidation of superoxide radicals, facilitated by the interaction of ionizing photon irradiation with TiOኼ NPs, is expected but could not be verified. Future research may verify the origin of the rise in fluorescencent SOSG to be hydrated electrons or singlet oxygen.

Polymeric micelles have a promising future in the treatment of cancer patients, and particularly as carriers in chemotherapy. The effectiveness of the micelles can be determined when their fate in vivo is known. Radiolabeling the micelles with diagnostic radionuclides allows for determination of their biodistribution and pharmacokinetics using nuclear imaging techniques. Besides imaging, therapeutic radionuclides can also possibly be applied to allow combination of radionuclide therapy and chemotherapy. In previous work, polymeric micelles were radiolabeled with ¹⁷⁷Lu, a therapeutic radionuclide. ¹⁷⁷Lu emits both β⁻ and γ radiation, β⁻ radiation can damage the tumor while the emitted γ radiation can be used for imaging purposes. For the clinical application of such micelles it is vital to determine their radiolabeling stability, i.e. the degree to which the radionuclides remain encapsulated in the micelles when exposed to serum or other conditions such as challenging with chelators. Size Exclusion Chromatography is a commonly used method to determine the radiolabeling stability but has proven to give inconsequent results when carried out in serum. In this research the radiolabeling stability of polymeric micelles was determined using Thin Layer Chromatography and DTPA as a competing chelator. Silica coated aluminum strips were loaded with sample, run using several different mobile phases, and analyzed through phosphor imaging and automated gamma counting. These experiments were then repeated under serum conditions. Experimental results of Thin Layer Chromatography with ¹⁷⁷Lu radiolabeled PCL-PEO micelles were then compared with Size Exclusion Chromatography results from earlier research. It was concluded that while the mobile phase used can influence the radiolabeling stability, Thin Layer Chromatography can provide an excellent method of efficiently determining radiolabeling stabilities of radiolabeled micelles under non-serum and serum conditions.

A polymersome is a type of nanocarrier made of amphiphilic block copolymers, consisting of a hydrophobic bilayer, a hydrophilic brush-like outer shell and a hollow, aqueous core, which is formed through self-assembly. Polymersomes could be useful in the treatment of cancer as carrier to deliver and release drugs or radionuclides to tumours locally to reduce them without damaging healthy tissue. For this purpose, it could rely on the Enhanced Permeation and Retention (EPR) effect to accumulate in tumours, which requires a long blood circulation time. Reports have shown that while the circulation half-life in healthy mice is in the order of hours, it decreases to the order of minutes in diseased mice, preventing any uptake of polymersomes in tumours. So, more research needs to be done on the in vivo biodistribution for each type of polymersome to assess whether it is suitable for radiotherapy. Thus far, imaging for polymersome in vivo biodistribution mostly relies on the use of In-111 and Single Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) as imaging technique. In this report it is researched whether it is possible to load gallium-68 (positron emitter, half-life 67.71 min) into poly(1,2-butadiene)-b-poly(ethylene oxide) {PBd(1800 g mol^-1)-b-PEO(600 g mol^-1)} polymersomes using an active loading method, which has not been done so far. This would allow short-term imaging using Positron Emission Tomography (PET) as an alternative imaging technique. PET has a much higher sensitivity than SPECT, which allows better image quality or shorter scan times. These advantages make PET better than SPECT for clinical use.Using Ga-68 as the positron emitting source has the advantage on being able to rely on a germanium-68/gallium-68 generator to produce Ga-68 on-site and being independent of external radionuclide suppliers.In this report the pH dependency of the formation of complex of Ga-68 with a lipophilic ligand was researched, the transfer of Ga-68 from the lipophilic ligand to a hydrophilic chelator was optimised, and loading experiments of Ga-68 into polymersomes were conducted. It was demonstrated that it is indeed possible to load Ga-68 into polymersomes, and maximum loading efficiencies of up to 36% were found. It is argued that the low loading efficiency could be caused by an unexpectedly thick hydrophobic bilayer of the prepared polymersomes, and possibly by a low amount of encapsulated hydrophilic chelator compared to the applied amount of lipophilic ligand. But more research needs to be done to confirm these observations.